{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T17:24:04Z","timestamp":1772213044229,"version":"3.50.1"},"reference-count":55,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T00:00:00Z","timestamp":1643932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 109-2314-B-468-005"],"award-info":[{"award-number":["MOST 109-2314-B-468-005"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neurogenesis is a physiological response after cerebral ischemic injury to possibly repair the damaged neural network. Therefore, promoting neurogenesis is very important for functional recovery after cerebral ischemic injury. Our previous research indicated that hyperbaric oxygen therapy (HBOT) exerted neuroprotective effects, such as reducing cerebral infarction volume. The purposes of this study were to further explore the effects of HBOT on the neurogenesis and the expressions of cell migration factors, including the stromal cell-derived factor 1 (SDF1) and its target receptor, the CXC chemokine receptor 4 (CXCR4). Thirty-two Sprague\u2013Dawley rats were divided into the control or HBO group after receiving transient middle cerebral artery occlusion (MCAO). HBOT began to intervene 24 h after MCAO under the pressure of 3 atmospheres for one hour per day for 21 days. Rats in the control group were placed in the same acrylic box without HBOT during the experiment. After the final intervention, half of the rats in each group were cardio-perfused with ice-cold saline followed by 4% paraformaldehyde under anesthesia. The brains were removed, dehydrated and cut into serial 20\u03bcm coronal sections for immunofluorescence staining to detect the markers of newborn cell (BrdU+), mature neuron cell (NeuN+), SDF1, and CXCR4. The affected motor cortex of the other half rats in each group was separated under anesthesia and used to detect the expressions of brain-derived neurotrophic factor (BDNF), SDF1, and CXCR4. Motor function was tested by a ladder-climbing test before and after the experiment. HBOT significantly enhanced neurogenesis in the penumbra area and promoted the expressions of SDF1 and CXCR4. The numbers of BrdU+\/SDF1+, BrdU+\/CXCR4+, and BrdU+\/NeuN+ cells and BDNF concentrations in the penumbra were all significantly increased in the HBO group when compared with the control group. The motor functions were improved in both groups, but there was a significant difference between groups in the post-test. Our results indicated that HBOT for 21 days enhanced neurogenesis and promoted cell migration toward the penumbra area in transient brain ischemic rats. HBOT also increased BDNF expression, which might further promote the reconstructions of the impaired neural networks and restore motor function.<\/jats:p>","DOI":"10.3390\/ijms23031780","type":"journal-article","created":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T11:35:17Z","timestamp":1643974517000},"page":"1780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The SDF1-CXCR4 Axis Is Involved in the Hyperbaric Oxygen Therapy-Mediated Neuronal Cells Migration in Transient Brain Ischemic Rats"],"prefix":"10.3390","volume":"23","author":[{"given":"Ray-Yau","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Physical Therapy and Assistive Technology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yea-Ru","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Assistive Technology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heng-Chih","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy, Asia University, Taichung 413, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1159\/000330462","article-title":"The ischemic penumbra: Correlates in imaging and implications for treatment of ischemic stroke","volume":"32","author":"Heiss","year":"2011","journal-title":"Cerebrovasc. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.scr.2013.06.006","article-title":"Cortical lesion stimulates adult subventricular zone neural progenitor cell proliferation and migration to the site of injury","volume":"11","author":"Saha","year":"2013","journal-title":"Stem Cell Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"576444","DOI":"10.3389\/fncel.2020.576444","article-title":"Beyond the Hippocampus and the SVZ: Adult Neurogenesis Throughout the Brain","volume":"14","author":"Jurkowski","year":"2020","journal-title":"Front. Cell Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s12975-019-00717-8","article-title":"Adult Neurogenesis in the Subventricular Zone and Its Regulation After Ischemic Stroke: Implications for Therapeutic Approaches","volume":"11","author":"Dillen","year":"2020","journal-title":"Transl. Stroke Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"434","DOI":"10.3389\/fncel.2014.00434","article-title":"Subventricular zone progenitors in time and space: Generating neuronal diversity","volume":"8","author":"Sequerra","year":"2014","journal-title":"Front. Cell Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"18117","DOI":"10.1073\/pnas.0408258102","article-title":"Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha\/CXC chemokine receptor 4 pathway","volume":"101","author":"Imitola","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jneuroim.2008.04.010","article-title":"Enhanced expression of the CXCl12\/SDF-1 chemokine receptor CXCR7 after cerebral ischemia in the rat brain","volume":"198","author":"Schulz","year":"2008","journal-title":"J. Neuroimmunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"166","DOI":"10.2174\/138945012799201603","article-title":"Roles of chemokine CXCL12 and its receptors in ischemic stroke","volume":"13","author":"Wang","year":"2012","journal-title":"Curr. Drug Targets"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.brainres.2007.11.068","article-title":"SDF-1alpha\/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model","volume":"1195","author":"Wang","year":"2008","journal-title":"Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.brainres.2007.08.091","article-title":"Role of SDF-1\/CXCR4 system in survival and migration of bone marrow stromal cells after transplantation into mice cerebral infarct","volume":"1183","author":"Shichinohe","year":"2007","journal-title":"Brain Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1007\/s12013-014-0103-5","article-title":"The effect of stromal cell-derived factor 1 in the migration of neural stem cells","volume":"70","author":"Xue","year":"2014","journal-title":"Cell Biochem. Biophys."},{"key":"ref_12","first-page":"239","article-title":"Stromal cell-derived factor-1 and its receptor CXCR4 in adult neurogenesis after cerebral ischemia","volume":"31","author":"Cui","year":"2013","journal-title":"Restor. Neurol. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1097\/01.WCB.0000073946.29308.55","article-title":"Inhibition of apoptosis by hyperbaric oxygen in a rat focal cerebral ischemic model","volume":"23","author":"Yin","year":"2003","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1161\/01.STR.0000173408.94728.79","article-title":"Hyperbaric oxygen reduces blood-brain barrier damage and edema after transient focal cerebral ischemia","volume":"36","author":"Veltkamp","year":"2005","journal-title":"Stroke"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1179\/174313209X389857","article-title":"Hyperbaric oxygen therapy and cerebral ischemia: Neuroprotective mechanisms","volume":"31","author":"Matchett","year":"2009","journal-title":"Neurol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1152\/japplphysiol.91054.2008","article-title":"Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo","volume":"106","author":"Milovanova","year":"2009","journal-title":"J. Appl. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s00421-009-1229-9","article-title":"Hyperbaric oxygenation alleviates MCAO-induced brain injury and reduces hydroxyl radical formation and glutamate release","volume":"108","author":"Yang","year":"2010","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.brainres.2011.07.064","article-title":"Oxygen therapy improves energy metabolism in focal cerebral ischemia","volume":"1415","author":"Sun","year":"2011","journal-title":"Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e5187","DOI":"10.1590\/1414-431x20165187","article-title":"Effect of hyperbaric oxygenation on mitochondrial function of neuronal cells in the cortex of neonatal rats after hypoxic-ischemic brain damage","volume":"49","author":"Yang","year":"2016","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1016\/j.biopha.2018.10.025","article-title":"Effect of hyperbaric oxygen on the permeability of the blood-brain barrier in rats with global cerebral ischemia\/reperfusion injury","volume":"108","author":"Li","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"147097","DOI":"10.1016\/j.brainres.2020.147097","article-title":"Effects of repetitive hyperbaric oxygen therapy on neuroprotection in middle cerebral artery occlusion rats","volume":"1748","author":"Chang","year":"2020","journal-title":"Brain Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"136","DOI":"10.3892\/br.2016.673","article-title":"Effect of hyperbaric oxygen on lipid peroxidation and visual development in neonatal rats with hypoxia-ischemia brain damage","volume":"5","author":"Chen","year":"2016","journal-title":"Biomed. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.4103\/1673-5374.112859","article-title":"Hyperbaric oxygen treatment promotes neural stem cell proliferation in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage","volume":"8","author":"Feng","year":"2013","journal-title":"Neural Regen. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"512978","DOI":"10.1155\/2013\/512978","article-title":"Long course hyperbaric oxygen stimulates neurogenesis and attenuates inflammation after ischemic stroke","volume":"2013","author":"Lee","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.nbd.2012.11.003","article-title":"Delayed hyperbaric oxygen therapy induces cell proliferation through stabilization of cAMP responsive element binding protein in the rat model of MCAo-induced ischemic brain injury","volume":"51","author":"Mu","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1161\/STROKEAHA.114.005116","article-title":"Delayed hyperbaric oxygen therapy promotes neurogenesis through reactive oxygen species\/hypoxia-inducible factor-1\u03b1\/\u03b2-catenin pathway in middle cerebral artery occlusion rats","volume":"45","author":"Hu","year":"2014","journal-title":"Stroke"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1097\/WNR.0000000000000901","article-title":"Hyperbaric oxygen promotes neural stem cell proliferation by activating vascular endothelial growth factor\/extracellular signal-regulated kinase signaling after traumatic brain injury","volume":"28","author":"Yang","year":"2017","journal-title":"NeuroReport"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1161\/STROKEAHA.107.510982","article-title":"Functional integration of newly generated neurons into striatum after cerebral ischemia in the adult rat brain","volume":"39","author":"Hou","year":"2008","journal-title":"Stroke"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nn.2473","article-title":"Ischemia-induced neurogenesis of neocortical layer 1 progenitor cells","volume":"13","author":"Ohira","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.expneurol.2010.08.006","article-title":"Increased subventricular zone-derived cortical neurogenesis after ischemic lesion","volume":"226","author":"Kreuzberg","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/978-3-030-74046-7_8","article-title":"Intervention of Brain-Derived Neurotrophic Factor and Other Neurotrophins in Adult Neurogenesis","volume":"1331","author":"Ribeiro","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/stem.2947","article-title":"Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain","volume":"37","author":"Lin","year":"2019","journal-title":"Stem Cells"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wang, X., Mao, X., Xie, L., Sun, F., Greenberg, D.A., and Jin, K. (2012). Conditional depletion of neurogenesis inhibits long-term recovery after experimental stroke in mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038932"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"17314","DOI":"10.1523\/JNEUROSCI.2129-13.2013","article-title":"Conditional ablation of neuroprogenitor cells in adult mice impedes recovery of poststroke cognitive function and reduces synaptic connectivity in the perforant pathway","volume":"33","author":"Sun","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.4161\/cc.24984","article-title":"Lineage progression from stem cells to new neurons in the adult brain ventricular-subventricular zone","volume":"12","author":"Ponti","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.expneurol.2013.06.017","article-title":"Stromal derived growth factor-1 (CXCL12) modulates synaptic transmission to immature neurons during post-ischemic cerebral repair","volume":"248","author":"Ardelt","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"590","DOI":"10.3389\/fnins.2017.00590","article-title":"The Role of SDF-1\/CXCR4\/CXCR7 in Neuronal Regeneration after Cerebral Ischemia","volume":"11","author":"Cheng","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s12031-014-0279-6","article-title":"Chemotactic responses of neural stem cells to SDF-1\u03b1 correlate closely with their differentiation status","volume":"54","author":"Chen","year":"2014","journal-title":"J. Mol. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"173821","DOI":"10.1016\/j.ejphar.2020.173821","article-title":"Attenuating effect of paroxetine on memory impairment following cerebral ischemia-reperfusion injury in rat: The involvement of BDNF and antioxidant capacity","volume":"893","author":"Sheikholeslami","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7260130","DOI":"10.1155\/2017\/7260130","article-title":"Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection","volume":"2017","author":"Phillips","year":"2017","journal-title":"Neural Plast."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1097\/CM9.0000000000000115","article-title":"Hyperbaric oxygen improves functional recovery of rats after spinal cord injury via activating stromal cell-derived factor-1\/CXC chemokine receptor 4 axis and promoting brain-derived neurothrophic factor expression","volume":"132","author":"Meng","year":"2019","journal-title":"Chin. Med. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1177\/0300060519827173","article-title":"The stromal cell-derived factor-1 \u03b1 (SDF-1\u03b1)\/cysteine-X-cysteine chemokine receptor 4 (CXCR4) axis: A possible prognostic indicator of acute ischemic stroke","volume":"47","author":"Huang","year":"2019","journal-title":"J. Int. Med. Res."},{"key":"ref_43","first-page":"471","article-title":"Hyperbaric oxygen can induce neuroplasticity and improve cognitive functions of patients suffering from anoxic brain damage","volume":"33","author":"Hadanny","year":"2015","journal-title":"Restor. Neurol. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.clinbiochem.2017.12.001","article-title":"Hyperbaric oxygen ameliorated the lesion scope and nerve function in acute spinal cord injury patients: A retrospective study","volume":"53","author":"Tan","year":"2018","journal-title":"Clin. Biochem."},{"key":"ref_45","first-page":"93","article-title":"Hyperbaric oxygen therapy improves neurocognitive functions of post-stroke patients\u2014A retrospective analysis","volume":"38","author":"Hadanny","year":"2020","journal-title":"Restor Neurol. Neurosci."},{"key":"ref_46","first-page":"1","article-title":"Hypoxia and aging","volume":"51","author":"Yeo","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Hadanny, A., and Efrati, S. (2020). The Hyperoxic-Hypoxic Paradox. Biomolecules, 10.","DOI":"10.3390\/biom10060958"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"104416","DOI":"10.1016\/j.yexmp.2020.104416","article-title":"HIF-1\u03b1\/SDF-1\/CXCR4 axis reduces neuronal apoptosis via enhancing the bone marrow-derived mesenchymal stromal cell migration in rats with traumatic brain injury","volume":"114","author":"Guo","year":"2020","journal-title":"Exp. Mol. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1249\/MSS.0000000000000310","article-title":"Quercetin enhances exercise-mediated neuroprotective effects in brain ischemic rats","volume":"46","author":"Chang","year":"2014","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1161\/01.STR.17.4.738","article-title":"A model of focal ischemic stroke in the rat: Reproducible extensive cortical infarction","volume":"17","author":"Chen","year":"1986","journal-title":"Stroke"},{"key":"ref_51","first-page":"100","article-title":"Middle cerebral artery occlusion in rats: A neurological and pathological evaluation of a reproducible model","volume":"31","author":"Menzies","year":"1992","journal-title":"Neurosurgery"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00421-011-1976-2","article-title":"Effects of hyperbaric oxygenation on oxidative stress in acute transient focal cerebral ischemic rats","volume":"112","author":"Wang","year":"2012","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/j.neuroscience.2009.01.011","article-title":"Hyperbaric oxygen preconditioning reduces ischemia-reperfusion injury by inhibition of apoptosis via mitochondrial pathway in rat brain","volume":"159","author":"Li","year":"2009","journal-title":"Neuroscience"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.neuroscience.2003.08.031","article-title":"Motor balance and coordination training enhances functional outcome in rat with transient middle cerebral artery occlusion","volume":"123","author":"Ding","year":"2004","journal-title":"Neuroscience"},{"key":"ref_55","unstructured":"Paxinos, G., and Watson, C. (2007). The rat brain in stereotaxic coordinates. Plates and Figures, Harcourt Brace Jovanovich. [6th ed.]."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1780\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:14:01Z","timestamp":1760134441000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,4]]},"references-count":55,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031780"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031780","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,4]]}}}